The present invention relates to novel compounds, and therapeutically acceptable salts thereof, which inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal inflammatory diseases. In further aspects, the invention relates to compounds of the invention for use in therapy; to processes for preparation of such new compounds; to pharmaceutical compositions containing at least one compound of the invention, or a therapeutically acceptable salt thereof, as active ingredient; and to the use of the active compounds in the manufacture of medicaments for the medical use indicated above.
Benzimidazole derivatives of the following formula, active as anti-ulcer agents, are disclosed in EP-B-0 266 326 and in U.S. Pat. No. 5,106,862: 
wherein R1 is i.a. an aryl group of the formula: 
in which each of R7, R8 and R9 independently represents i.a. H or C1-C6 alkyl, or halogen;
R2 is i.a. H;
R3 is i.a. H or C1-C6 alkyl;
n is an integer 0-6;
R4, R5 and R6 are H or C1-C6 alkyl;
A is alkylene up to 6 carbon atoms optionally interrupted by a hetero atom such as O or N.
For a review of the pharmacology of the gastric acid pump (the H+, K+-ATPase), see Sachs et al. (1995) Annu. Rev. Pharmacol. Toxicol. 35: 277-305.
It has surprisingly been found that compounds of the Formula I, which are substituted benzimidazole derivatives in which the phenyl moiety is substituted with lower alkyl in 2- and 6-position, are particularly effective as inhibitors of the gastrointestinal H+, K+-ATPase and thereby as inhibitors of gastric acid secretion.
In one aspect, the invention thus relates to compounds of the general Formula I: 
or a pharmaceutically acceptable salt thereof, wherein
R1 is lower alkyl;
R2 is lower alkyl;
R3, which is in position 3, 4, or 5 of the phenyl ring, is
(a) H,
(b) halogen, or
(c) lower alkyl;
R4 is
(a) H, or
(b) lower alkyl;
X, which is connected to the heterocycle in the position 4 or 7, is
(a) NH, or
(b) O.
As used herein, the term xe2x80x9clower alkylxe2x80x9d denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said lower alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
The term xe2x80x9chalogenxe2x80x9d includes fluoro, chloro, bromo and iodo.
Both pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers are within the scope of the invention. It should be understood that all the diastereomeric forms possible (pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers) are within the scope of the invention. Also included in the invention are derivatives of the compounds of the Formula I which have the biological function of the compounds of the Formula I.
Depending on the process conditions the end products of the Formula I are obtained either in neutral or salt form. Both the free base and the salts of these end products are within the scope of the invention.
Acid addition salts of the new compounds may in a manner known per se be transformed into the free base using basic agents such as alkali or by ion exchange. The free base obtained may also form salts with organic or inorganic acids.
In the preparation of acid addition salts, preferably such acids are used which form suitably therapeutically acceptable salts. Examples of such acids are hydrohalogen acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxyl or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybensoic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, halogenbensenesulfonic acid, toluenesulfonic acid or naphthalenesulfonic acid.
Preferred compounds according to the invention are those of the formula I wherein R1 is CH3 or CH2CH3; R2 is CH3 or CH2CH3; R3 is H, 4-F or 4-Cl; R4 is H or CH3 and X is NH or O connected to the heterocycle in the 4-position.
Particularly preferred compounds according to the invention are:
4-(2,6-dimethylbenzylamino)-2-methylbenzimidazole;
4-(2,6-dimethylbenzyloxy)-2-methylbenzimidazole;
4-(2,6-dimethyl-4-fluorobenzylamino)-2-methylbenzimidazole;
4-(2,6-dimethyl-4-fluorobenzyloxy)-2-methylbenzimidazole;
4-(2,6-dimethylbenzylamino)-1,2-dimethylbenzimidazole;
4-(2-ethyl-6-methylbenzylamino)-2-methylbenzimidazole;
4-(2,6-diethylbenzylamino)-2-methylbenzimidazole;
4-(2,6-dimethyl-4-fluorobenzylamino)-1,2-dimethylbenzimidazole;
4-(2,6-dimethyl-4-fluorobenzyloxy)-1,2-dimethylbenzimidazole.
The present invention also provides the following processes A to C for the manufacture of compounds with the general Formula I:
Process A
Process A for manufacture of compounds with the general Formula I comprises the following steps:
a) Compounds of the general Formula II 
wherein X1 is NH2 or OH connected to the heterocycle in the position 4 or 7 and R4 is as defined for Formula I, can be reacted with compounds of the general Formula III: 
wherein R1, R2 and R3 are as defined for Formula I and Y is a leaving group, such as a halide, tosyloxy or mesyloxy, to the compounds of the Formula I.
It is convenient to conduct this reaction in an inert solvent, e.g. acetone, acetonitrile, dimethoxyethane, methanol, ethanol or dimethylformamide with or without a base. The base is e.g. an alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide; a sodium alcoholate, such as sodium methoxide and sodium ethoxide; an alkali metal hydride such as sodium hydride and potassium hydride; an alkali metal carbonate, such as potassium carbonate and sodium carbonate; or an organic amine, such as triethylamin.
Process B
Process B for manufacture of compounds with the general Formula I comprises the following step:
A compound of the Formula IV: 
wherein R4 is as defined for Formula I and the NH2 group is connected to the heterocycle in the position 4 or 7, can be reacted with compounds of the general Formula V: 
wherein R1, R2 and R3 are as defined for Formula I, in the presence of a Lewis acid e.g. zinc chloride to the compounds of the Formula VI: 
wherein R4 is as defined for Formula I and the imine nitrogen is connected to the heterocycle in the position 4 or 7, whereby the compounds of the general Formula VI are reduced e.g. by using sodium borhydride or sodiumcyano borhydride to compounds of the general Formula I. The reactions can be carried out under standard conditions in an inert solvent e.g. methanol orethanol.
Process C
Compounds of the general Formula I wherein R4 is xe2x80x9clower alkylxe2x80x9d can be made by alkylation of compounds of the general Formula I wherein R4 is H in an inert solvent, e.g. acetonitrile or acetone, with or without base with compounds of the general Formula VII:
R4X2 VII
wherein R4 is as defined for Formula I and X2 is a leaving group e.g. a halide, mesylate or tosylate. The base is e.g. an alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide; a sodium alcoholate, such as sodium methoxide and sodium ethoxide; an alkali metal hydride such as sodium hydride and potassium hydride; an alkali metal carbonate, such as potassium carbonate and sodium carbonate; or an organic amine, such as triethylamine.
In a further aspect, the invention relates to compounds of the formula I for use in therapy, in particular for use against gastrointestinal inflammatory diseases. The invention also provides the use of a compound of the formula I in the manufacture of a medicament for the inhibition of gastric acid secretion, or for the treatment of gastrointestinal inflammatory diseases.
The compounds according to the invention may thus be used for prevention and treatment of gastrointestinal inflammatory diseases, and gastric acid-related diseases in mammals including man, such as gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis and Zollinger-Ellison syndrome. Furthermore, the compounds may be used for treatment of other gastrointestinal disorders where gastric antisecretory effect is desirable, e.g. in patients with gastrinomas, and in patients with acute upper gastrointestinal bleeding. They may also be used in patients in intensive care situations, and pre-and postoperatively to prevent acid aspiration and stress ulceration.
In yet a further aspect, the invention relates to pharmaceutical compositions containing at least one compound of the invention, or a therapeutically acceptable salt thereof, as active ingredient.
The compounds of the invention can also be used in formulations together with other active ingredients, e.g. antibiotics such as amoxicillin.
For clinical use,.the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. The pharmaceutical formulation contains a compound of the invention in combination with one or more pharmaceutically acceptable ingredients. The carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule. These pharmaceutical preparations are a further object of the invention. Usually the amount of active compounds is between 0.1-95% by weight of the preparation, preferably between 0.1-20% by weight in preparations for parenteral use and preferably between 0.1 and 50% by weight in preparations for oral administration.
In the preparation of pharmaceutical formulations containing a compound of the present invention in the form of dosage units for oral administration the compound selected may be mixed with solid, powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then processed into granules or pressed into tablets.
Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Hard gelatine capsules may contain granules of the active compound. Hard gelatine capsules may also contain the active compound in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.
Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing from 0.1% to 20% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent, preferably in a concentration from 0.1% to 10% by weight. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to by reconstituted with a suitable solvent extemporaneously before use.
The typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to 1000 mg per day of active substance.
The compounds according to the invention can also be used in formulations together with other active ingredients, e.g. for the treatment or prophylaxis of conditions involving infection by Helicobacter pylori of human gastric mucosa. Such other active ingredients may be antimicrobial agents, in particular:
b-lactam antibiotics such as amoxicillin, ampicillin, cephalothin, cefaclor or cefixime;
macrolides such as erythromycin, or clarithromycin;
tetracyclines such as tetracycline or doxycycline;
aminoglycosides such as gentamycin, kanamycin or amikacin;
quinolones such as norfloxacin, ciprofloxacin or enoxacin;
others such as metronidazole, nitrofurantoin or chloramphenicol; or
preparations containing bismuth salts such as bismuth subcitrate, bismuth subsalicylate, bismuth subcarbonate, bismuth subnitrate or bismuth subgallate.